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Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability.
Sci Transl Med. 2018 08 29; 10(456)ST

Abstract

Hyperphosphatemia is common in patients with chronic kidney disease and is increasingly associated with poor clinical outcomes. Current management of hyperphosphatemia with dietary restriction and oral phosphate binders often proves inadequate. Tenapanor, a minimally absorbed, small-molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), acts locally in the gastrointestinal tract to inhibit sodium absorption. Because tenapanor also reduces intestinal phosphate absorption, it may have potential as a therapy for hyperphosphatemia. We investigated the mechanism by which tenapanor reduces gastrointestinal phosphate uptake, using in vivo studies in rodents and translational experiments on human small intestinal stem cell-derived enteroid monolayers to model ion transport physiology. We found that tenapanor produces its effect by modulating tight junctions, which increases transepithelial electrical resistance (TEER) and reduces permeability to phosphate, reducing paracellular phosphate absorption. NHE3-deficient monolayers mimicked the phosphate phenotype of tenapanor treatment, and tenapanor did not affect TEER or phosphate flux in the absence of NHE3. Tenapanor also prevents active transcellular phosphate absorption compensation by decreasing the expression of NaPi2b, the major active intestinal phosphate transporter. In healthy human volunteers, tenapanor (15 mg, given twice daily for 4 days) increased stool phosphorus and decreased urinary phosphorus excretion. We determined that tenapanor reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux, an effect mediated exclusively via on-target NHE3 inhibition.

Authors+Show Affiliations

Ardelyx Inc., Fremont, CA 94555, USA. aking@ardelyx.com.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.Ardelyx Inc., Fremont, CA 94555, USA.University of Alberta, Edmonton, Alberta T6G 1C9, Canada.University of Alberta, Edmonton, Alberta T6G 1C9, Canada.Cardiovascular and Metabolic Disease (CVMD) Translational Medicine Unit, Early Clinical Development, Innovative Medicines and Early Development (IMED) Biotech Unit, AstraZeneca Gothenburg, 431 50 Mölndal, Sweden.Bioscience, CVMD, IMED Biotech Unit, AstraZeneca Gothenburg, 431 50 Mölndal, Sweden.Bioscience, CVMD, IMED Biotech Unit, AstraZeneca Gothenburg, 431 50 Mölndal, Sweden.Bioscience, CVMD, IMED Biotech Unit, AstraZeneca Gothenburg, 431 50 Mölndal, Sweden.Bioscience, CVMD, IMED Biotech Unit, AstraZeneca Gothenburg, 431 50 Mölndal, Sweden.CVMD, IMED Biotech Unit, AstraZeneca Gothenburg, 431 50 Mölndal, Sweden.Institute of Physiology, University of Zurich and National Center of Competence in Research Kidney Control of Homeostasis, CH-8057 Zurich, Switzerland.Institute of Physiology, University of Zurich and National Center of Competence in Research Kidney Control of Homeostasis, CH-8057 Zurich, Switzerland.Institute of Physiology, University of Zurich and National Center of Competence in Research Kidney Control of Homeostasis, CH-8057 Zurich, Switzerland.Department of Neuroscience, Physiology and Pharmacology, University College London, Royal Free Campus, London NW3 2PF, UK.Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.Institute of Physiology, University of Zurich and National Center of Competence in Research Kidney Control of Homeostasis, CH-8057 Zurich, Switzerland.University of Alberta, Edmonton, Alberta T6G 1C9, Canada.Ardelyx Inc., Fremont, CA 94555, USA.

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30158152

Citation

King, Andrew J., et al. "Inhibition of Sodium/hydrogen Exchanger 3 in the Gastrointestinal Tract By Tenapanor Reduces Paracellular Phosphate Permeability." Science Translational Medicine, vol. 10, no. 456, 2018.
King AJ, Siegel M, He Y, et al. Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med. 2018;10(456).
King, A. J., Siegel, M., He, Y., Nie, B., Wang, J., Koo-McCoy, S., Minassian, N. A., Jafri, Q., Pan, D., Kohler, J., Kumaraswamy, P., Kozuka, K., Lewis, J. G., Dragoli, D., Rosenbaum, D. P., O'Neill, D., Plain, A., Greasley, P. J., Jönsson-Rylander, A. C., ... Caldwell, J. S. (2018). Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Science Translational Medicine, 10(456). https://doi.org/10.1126/scitranslmed.aam6474
King AJ, et al. Inhibition of Sodium/hydrogen Exchanger 3 in the Gastrointestinal Tract By Tenapanor Reduces Paracellular Phosphate Permeability. Sci Transl Med. 2018 08 29;10(456) PubMed PMID: 30158152.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. AU - King,Andrew J, AU - Siegel,Matthew, AU - He,Ying, AU - Nie,Baoming, AU - Wang,Ji, AU - Koo-McCoy,Samantha, AU - Minassian,Natali A, AU - Jafri,Qumber, AU - Pan,Deng, AU - Kohler,Jill, AU - Kumaraswamy,Padmapriya, AU - Kozuka,Kenji, AU - Lewis,Jason G, AU - Dragoli,Dean, AU - Rosenbaum,David P, AU - O'Neill,Debbie, AU - Plain,Allein, AU - Greasley,Peter J, AU - Jönsson-Rylander,Ann-Cathrine, AU - Karlsson,Daniel, AU - Behrendt,Margareta, AU - Strömstedt,Maria, AU - Ryden-Bergsten,Tina, AU - Knöpfel,Thomas, AU - Pastor Arroyo,Eva M, AU - Hernando,Nati, AU - Marks,Joanne, AU - Donowitz,Mark, AU - Wagner,Carsten A, AU - Alexander,R Todd, AU - Caldwell,Jeremy S, PY - 2016/12/21/received PY - 2017/10/31/revised PY - 2018/03/06/accepted PY - 2018/8/31/entrez PY - 2018/8/31/pubmed PY - 2019/10/12/medline JF - Science translational medicine JO - Sci Transl Med VL - 10 IS - 456 N2 - Hyperphosphatemia is common in patients with chronic kidney disease and is increasingly associated with poor clinical outcomes. Current management of hyperphosphatemia with dietary restriction and oral phosphate binders often proves inadequate. Tenapanor, a minimally absorbed, small-molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), acts locally in the gastrointestinal tract to inhibit sodium absorption. Because tenapanor also reduces intestinal phosphate absorption, it may have potential as a therapy for hyperphosphatemia. We investigated the mechanism by which tenapanor reduces gastrointestinal phosphate uptake, using in vivo studies in rodents and translational experiments on human small intestinal stem cell-derived enteroid monolayers to model ion transport physiology. We found that tenapanor produces its effect by modulating tight junctions, which increases transepithelial electrical resistance (TEER) and reduces permeability to phosphate, reducing paracellular phosphate absorption. NHE3-deficient monolayers mimicked the phosphate phenotype of tenapanor treatment, and tenapanor did not affect TEER or phosphate flux in the absence of NHE3. Tenapanor also prevents active transcellular phosphate absorption compensation by decreasing the expression of NaPi2b, the major active intestinal phosphate transporter. In healthy human volunteers, tenapanor (15 mg, given twice daily for 4 days) increased stool phosphorus and decreased urinary phosphorus excretion. We determined that tenapanor reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux, an effect mediated exclusively via on-target NHE3 inhibition. SN - 1946-6242 UR - https://www.unboundmedicine.com/medline/citation/30158152/Inhibition_of_sodium/hydrogen_exchanger_3_in_the_gastrointestinal_tract_by_tenapanor_reduces_paracellular_phosphate_permeability_ DB - PRIME DP - Unbound Medicine ER -